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      Metabolic Checkpoints: Novel Avenues for Immunotherapy of Cancer

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          Abstract

          Novel therapies targeting immune checkpoint molecules have redefined the treatment of cancer at advanced stages and brought hope to millions of patients worldwide. Monoclonal antibodies targeting immune-inhibitory receptors often lead to complete and objective responses as well as to durable progression-free survival where all other therapeutic approaches fail. Yet, many tumors show significant resistance to checkpoint blockade through mechanisms that are only starting to come to light. An alluring alternative strategy to reinvigorate anticancer immune responses comes from the emerging field of immuno-metabolism. Over the past few years, numerous studies revealed that many well-known metabolic playmakers also serve as critical checkpoints in immune homeostasis and immunity against tumors. Here, we survey recent insights into the intimate and intertwining links between T cell metabolic programs and environmental cues in the tumor milieu. Transferring these new findings from the bench to the bedside may soon entirely re-shape the field of cancer immunotherapy and significantly improve the lives of patients.

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          Most cited references19

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          The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function.

          CD4 T cell activation leads to proliferation and differentiation into effector (Teff) or regulatory (Treg) cells that mediate or control immunity. While each subset prefers distinct glycolytic or oxidative metabolic programs in vitro, requirements and mechanisms that control T cell glucose uptake and metabolism in vivo are uncertain. Despite expression of multiple glucose transporters, Glut1 deficiency selectively impaired metabolism and function of thymocytes and Teff. Resting T cells were normal until activated, when Glut1 deficiency prevented increased glucose uptake and glycolysis, growth, proliferation, and decreased Teff survival and differentiation. Importantly, Glut1 deficiency decreased Teff expansion and the ability to induce inflammatory disease in vivo. Treg cells, in contrast, were enriched in vivo and appeared functionally unaffected and able to suppress Teff, irrespective of Glut1 expression. These data show a selective in vivo requirement for Glut1 in metabolic reprogramming of CD4 T cell activation and Teff expansion and survival. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Indoleamine 2,3 dioxygenase and metabolic control of immune responses.

            Sustained access to nutrients is a fundamental biological need, especially for proliferating cells, and controlling nutrient supply is an ancient strategy to regulate cellular responses to stimuli. By catabolizing the essential amino acid TRP, cells expressing the enzyme indoleamine 2,3 dioxygenase (IDO) can mediate potent local effects on innate and adaptive immune responses to inflammatory insults. Here, we discuss recent progress in elucidating how IDO activity promotes local metabolic changes that impact cellular and systemic responses to inflammatory and immunological signals. These recent developments identify potential new targets for therapy in a range of clinical settings, including cancer, chronic infections, autoimmune and allergic syndromes, and transplantation. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Unraveling the Complex Interplay Between T Cell Metabolism and Function.

              Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development, activation, function, differentiation, and survival. After naive T cells are activated, increased demands for metabolic currency in the form of ATP, as well as biomass for cell growth, proliferation, and the production of effector molecules, are met by rewiring cellular metabolism. Consequently, pharmacological strategies are being developed to perturb or enhance selective metabolic processes that are skewed in immune-related pathologies. Here we review the most recent advances describing the metabolic changes that occur during the T cell lifecycle. We discuss how T cell metabolism can have profound effects on health and disease and where it might be a promising target to treat a variety of pathologies.
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                Author and article information

                Contributors
                URI : https://frontiersin.org/people/u/101581
                URI : https://frontiersin.org/people/u/460720
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                07 August 2018
                2018
                : 9
                : 1816
                Affiliations
                [1] 1Institute for Immunology, Ludwig-Maximilians University , Munich, Germany
                [2] 2Department of General, Visceral and Transplantation Surgery, Ludwig-Maximilians University , Munich, Germany
                [3] 3German Cancer Consortium (DKTK), Partner Site Munich , Munich, Germany
                Author notes

                Edited by: Salem Chouaib, Institut Gustave Roussy, France

                Reviewed by: Zong Sheng Guo, University of Pittsburgh, United States; Carlos Alfaro, NavarraBiomed, Spain; Abhishek D. Garg, KU Leuven, Belgium

                *Correspondence: Ivan Shevchenko, ivshevch87@ 123456gmail.com

                Specialty section: This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2018.01816
                6090142
                30131808
                deb38a23-0424-40dd-b023-7e9289b49a4d
                Copyright © 2018 Shevchenko and Bazhin.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 30 April 2018
                : 23 July 2018
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 40, Pages: 6, Words: 4429
                Categories
                Immunology
                Mini Review

                Immunology
                metabolic checkpoints,immune checkpoints,cancer immunotherapy,pd-1,checkpoint blockade,mammalian target of rapamycin pathway

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